Hematopoietic stem cell transplantation (HSCT) has become an important treatment option for patients with sickle cell anemia or thalassemia. While the source of HSCT is usually bone marrow from an HLA identical sibling, cord blood (CB) may prove to be an important resource. CB can contain sufficient numbers of hematopoietic stem cells for engraftment post myeloablative therapy, can be used without a complete HLA match, and CB has less chance of inducing graft-versus-host disease (GVHD) than bone marrow. To increase the availability of CB for these purposes, a number of CB banks have been developed. However, none have focused on sibling donor cord blood (SDCB) collection, a process which requires a unique set of procedures to accommodate collection at remote sites, and none have extensive experience working with families who have a child with sickle cell anemia or thalassemia. This revised application contains two specific aims: (1) to collect sibling-donor CB in families that currently have a child with sickle cell anemia or thalassemia and (2) to use these CBs to conduct the first multi-center prospective pilot study of CB transplantation in children with these two diseases. The SDCB Program at CHORI will follow procedures that comply with standards for cord blood banking. The success of our feasibility study has demonstrated that our program can collect a sufficient number of Cbs to conduct the pilot transplantation study. Scientific questions regarding engraftment failure, disease recurrence, HLA compatibility, and the requirement for a critical number of HSCs are addressed in the application. We will test the hypothesis that a novel immunosuppressive conditioning regimen (fludarabine, cyclophosphamide and busulfan) and post transplant therapy (mycophenalate mofetil and cyclosporine) will improve engraftment rates and prevent disease recurrence. The effect of SDCB transplantation on hematologic parameters and GVHD will be monitored. Information for this pilot study will be used to design new approaches employing SDCB transplantation for patients with hemoglobinopathies. In summary, the ultimate goal of our proposal will be to focus our SDCB program on collection of CBs from families that have a child with a hemoglobinopathy and to use these CBs to evaluate the role of CB transplants in these children. We anticipate that our project will advance the field of SDCB transplantation from case reports to clinical investigation and, will provide a rational basis for further studies of CB transplantation in children with hemoglobinopathies.